DOPAnization of α-synuclein exacerbates dopaminergic neurodegeneration in the substantia nigra

Parkinson's disease (PD) is characterized by the selective and progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN). Although abnormal forms and aggregates of the α-synuclein (αSyn) protein are considered to cause PD, the underlying mechanisms of the preferential death of dopaminergic neurons are largely unknown. We recently reported that a tyrosine hydroxylase post-translationally converted a tyrosine residue of αSyn to dihydroxyphenylalanine (DOPA), termed DOPAnization, in the DAergic neurons of PD patients, which facilitated the formation of αSyn oligomers and increased neuronal toxicity in vitro. However, whether DOPAnized αSyn promotes the progressive death of DAergic neurons in vivo has not been determined. Here, we report that intranigral administration of in vitro-prepared DOPAnized αSyn oligomers induced more severe and progressive neurodegeneration in DAergic neurons than did the administration of unmodified αSyn aggregates. We also found that DOPAnized αSyn oligomers enhanced microglial activation, preceding the severe loss of SN neurons and their nigrostriatal projections. These findings suggest that DOPAnized αSyn in DAergic neurons plays a key role in the pathogenesis of PD.